Pharmacology of Muscarinic Receptor Blockade

Acetylcholine is an agonist at both muscarinic and nicotinic receptors

The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked

Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission

X

Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP

Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected.

XX

In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance

X

Atropine

Characteristics of Atropine

• Source– Atropa belladonna– Datura stramonium

• Known as Jamestown weed or jimsonweed

• Chemical nature– An alkaloid

• Alternate name is d,l-hyoscyamine• Nature of blockade

– Competitive

Response to ACh in the Presence of Atropine

Log dose of acetylcholine

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Atropine competitively inhibits muscarinic reponses to ACh

Actions of Atropine at Tissue Sites

• Eye – Sphincter muscle of the iris: mydriasis– Ciliary muscle: cycloplegia

Atropine limits focusing to distant objects

Accomodation is blocked by atropine

Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent

Changes in Accomodation and PupillaryDiameter after Administration of a Drug

0 1 5 3 0 4 5 6 0 7 5 9 00

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pup il diameter

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Time (minutes)

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Reproduced from Basic and Clinical Pharmacology

Actions of Atropine At Smooth Muscles And Glands

• Eye• Lacrimal glands• Mucus glands of the pharynx and nasal cavity• Bronchial smooth muscle• Gastric glands• Intestinal glands• Pancreas• Mucus glands of the respiratory tract• Lacrimal glands• Eccrine sweat glands

Cardiovascular Actions of Atropine

• Heart rate– Low dose– High dose

• Systemic blood vessels• Peripheral resistance• Cutaneous blood vessels

Response to Doses of Atropine

Reproduced from Basic and Clinical Pharmacology

M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in Response to

Nerve Impulse Flow

postsynaptic fiber

cardiac muscle fiber

ACh

ACh

ACh

(----)

M1

M2

M1Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow

postsynaptic fiber

cardiac muscle fiber

Pirenzepine is an M1 antagonist

x ACh ACh

ACh ACh

M1

M2

Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are among the results. Such actions are accentuated in the presence of inhibitors of AChE (they also block plasma pseudocholinesterase).

i.v. infusion

Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac and hypotensive responses to tachycardia and hypertension, mediated through the nicotinic receptors.

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x

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i.v. infusion

Effect Of Atropine in Relation to Dosage ...

Dose of Atropine

DOSE EFFECT

0.5 mg Slight decline in heart rate

Some dryness of mouth

Inhibition of sweating

Dose of Atropine

DOSE EFFECT

1.0 mg Definited dryness of mouth

Thirst

Inreased heart rate, sometimes preceded by slowing

Mild dilatation of pupil

Dose of Atropine

DOSE EFFECT

2.0 mg Rapid heart rate

Palpitation

Marked dryness of mouth

Dilated pupils

Some blurring of near vision

Dose of Atropine

DOSE EFFECT

5.0 mg All the previous symptoms are marked

Difficulty in speaking and swallowing

Restlessness and fatigue

Headache

Dry hot skin

Difficulty in micturition

Reduced intestinal peristalsis

Dose of Atropine

DOSE EFFECT

10 mg Previous symtoms are more marked

and more Pulse, rapid and weak

Iris practically obliterated

Vision very blurred

Skin flushed, hot, dry, and scarlet

Ataxia

Restlessness and excitement

Hallucinations and delirium

Coma

The previous five slides are reproduced fromGoodman and Gilman’s

The Pharmacological Basis of Therapeutics

Scopolamine (1)

• Source - Hyoscyamus niger (henbane)• Chemical nature of the molecule• Nature of blockade• Changes in the dose response curve of muscarinic

agonists in the presence of scopolamine• Lower doses of scopolamine (0.1 - 0.2 mg) produce

greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia

• Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine

Scopolamine (2)

• Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria

• In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine

• Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used

Therapeutic Uses of Antimuscarinic Agents

Therapeutic Uses of Muscarinic Antagonists (1)

• Cardiovascular System - atropine is generally used for the following cases– Improper use of choline esters

– Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct

– Hyperactive carotid sinus (syncope and severe bradycardia)

– Second degree heart block

Therapeutic Uses of Muscarinic Antagonists (2)

• Gastrointestinal Tract

– Peptic ulcers

• In Europe, Japan, and Canada, M1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used

• In the U.S. H2 histamine antagonists such as cimetidine are used

– Spasticity of the g.i. tract

• M3 muscarinic antagonists are being investigated

– Excessive salivation associated with heavy metal poisoning and parkinsonism

– Production of partial blockade of salivation in patients unable to swallow

Therapeutic Uses of Muscarinic Antagonists (3)

• Urinary Bladder

– Reverse spasm of the ureteral smooth muscle (renal colic)

– Increase bladder capacity in cases of enuresis

– Reduce urinary frequency in cases of hypertonic bladder

Therapeutic Uses of Muscarinic Antagonists (4)

• Central Nervous System– Parkinson’s disease– Motion sickness– Produce tranquilization and amnesia prior to

surgery and in certain cases such as labor (not a prominent use anymore)

– Anesthesia, to inhibit salivation (not a prominent use anymore)

– Prevent vagal reflexes induced by surgical manipulation of organs

Therapeutic Uses of Muscarinic Antagonists (5)

• Posioning by inhibitors of acetylcholinesterase• Mushroom poisoning due to muscarine• In conjunction with inhibitors of acetylcholinesterase

when they are used to promote recovery from neuromuscular blockade after surgery

• Injudicious use of choline esters• Prevent vagal reflexes induced by surgical

manipulation of visceral organs

Atropine is used for the above

Toxicity of Atropine

Contraindications to the Use Of Antimuscarinic Agents

• Narrow Angle Glaucoma

Flow of Aqueous and Its Escape From the Eye

Contraindications to the Use of Antimuscarinic Agents

• Narrow angle glaucoma• Hypertrophy of the prostate gland• Atony of the bladder• Atony of the G.I. Tract

Tertiary Muscarinic Antagonists and Their Uses

• Ophthalmic applications– Cyclopentolate– Tropicamide– Homatropine

• Parkinson’s disease– Benztropine– Trihexphenidyl

Tertiary Muscarinic Antagonists and Their Uses

• Used for antispasmodic purposes– Flavoxate - urinary bladder– Oxybutynin - urinary bladder– Tolterodine - urinary bladder– Dicyclomine– Oxyphencyclimine

In general, they are useful for spasms of the g.t. tract, bile duct, ureters,

Tolterodine

• Therapeutic use - reduce urinary urgency• Metabolism

– Cytochrome P450– Active metabolite is DD-01

• Drug interactions– Ketoconazole– Erythromycin

Quaternary Ammonium Antagonists (1)

• General characteristics• Pharmacology and therapeutic uses• Distinct side effects with high and sometimes

therapeutic doses

Quaternary Ammonium Antagonists (2)

• Methantheline (N+)• Propantheline (N +)• Methscopolamine (N +) • Homatropine methylbromide (N +)• Oxyphenonium (N +)

Quaternary Ammonium Antagonists (3)

• Anisotropine (N+)• Glycopyrrolate (N+)• Isopropamide (N+)• Mepenzolate (N+)• Ipratropium (N+)

Ipratropium

• Uses • Distinctiveness from atropine

M1 Muscarinic Receptor Antagonists

• Pirenzepine

– Blocks the M1 and the M4 receptor

– Its usefulness for peptic ulcer• Telenzepine

– Blocks the M1 receptor– Its usefulness for peptic ulcer

M2 Muscarinic Receptor Antagonists

• Tripitamine

– Blocks the M2 receptor

– Blocks the action of acetylcholine at cardiac muscle fibers

• Gallamine

– Blocks M2 muscarinic and the NN nicotinic sites

M3 Muscarinic Receptor Antagonist

• Darifenacin

– Blocks the M3 receptor

– Blocks the actions of acetylcholine at smooth muscles and glands

Drugs of Other Classes With Antimuscarinic Activity (1)

• Tricyclic antidepressants– Imipramine– Amitriptyline– Protriptyline– Others

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DEMONSTRATION

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Drugs of Other Classes With Antimuscarinic Activity (2)

• Phenothiazine Antipsychotic Agents– Chlorpromazine– Thioridazine– Perphenazine– Others

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DEMONSTRATION

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DEMONSTRATION

Drugs of Other Classes With Antimuscarinic Activity (3)

• Dibenzodiazepine antipsychotic agents– Clozapine– Olanzepine

• Dibenzoxazepine antipsychotic agents– Loxapine

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DEMONSTRATION

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DEMONSTRATION

Drugs of Other Classes With Antimuscarinic Activity (4)

• H1 Histamine receptor blocking agents

– Diphenhydramine– Dimenhydrinate

– Promethazine

– Carbinoxamine

– Dimenhydrinate

– Pyrlamine

– Tripelennamine

– Brompheniramine

– Chlorpheniramine

– Cyproheptadine

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DEMONSTRATION